Adamantylcarboxamidophenylalkanoic acids and esters thereof

ABSTRACT

1. A COMPOUND OF THE FORMULA   ADAMANT-1-YL-CO-NH-(PHENYLENE(-R3)(-R4))-CH(-R2)-(CH2)N-   COO-R1   WHEREIN R1 IS HYDROGEN OR LOWER ALKYL; R2 IS HYDROGEN OR LOWER ALKYL; R3 AND R4 ARE HYDROGEN, FLUORINE, CHLORINE, BROMINE LOWER ALKYL, LOWER ALKOXY, OR TRIFLUOROMETHYL; AND N IS 0 TO 1.

United States Patent Office 3,839,433 Patented Oct. 1, 1974 US. Cl.260518 R 7 Claims ABSTRACT OF THE DISCLOSUREAdamantylcarboxamidophenylalkanoic acids and their esters areanti-allergy and anti-inflammatory agents. An illustrative embodiment is2-(1-adamantylcarboxamido) phenylacetic acid.

CROSS-REFERENCE This is a continuation-in-part of Ser. No. 157,770 ofJune 28, 1971 now abandoned, which is a continuation of copendingapplications Ser. No. 22,406, filed Mar. 24, 1970 and Ser. No. 810,828,filed Mar. 26, 1969, both now abandoned.

SUMMARY OF THE INVENTION The present invention pertains to compounds ofthe formula I 5 1 R on (CH COOR wherein R and R are hydrogen or loweralkyl;

R and R are hydrogen, fluoro, chloro, bromo, lower alkyl, lower alkoxy,or trifluoromethyl; and

n is or 1 and to pharmaceutically acceptable non-toxic salts of thosecompounds wherein R is hydrogen.

The present invention also relates to novel methods and compositionsutilizing a compound of formula I for the treatment of allergic andinflammatory conditions.

DESCRIPTION OF THE PREFERRED EMBODIMENTS The term lower alkyl as usedherein alone or in combination, such as in lower alkoxy, means astraight or branched hydrocarbon chain of the formula C H wherein mrepresents an integer of from 1 to 4. Illustrative of such alkyl groupsare methyl, ethyl, propyl, isopropyl, n-, isoor t-butyl, and the like.Illustrative of lower alkoxy groups is methoxy, ethoxy, nor iso-propoxyor -butoxy, and the like, preferably methoxy. The preferred alkyl groupsfor substituent R are methyl and ethyl.

The term pharmaceutically acceptable non-toxic salts means salts formedwith inorganic or organic bases which themselves have no undesirablephysiological action in the usual dosages. Suitable salts are sodium,potassium, magnesium, calcium and ammonium salts and also salts withethylamine, triethylamine, ethanolamine, diethanolamine,ethylenediamine, pyrrolidine, etc.

The unsubstituted and substituted adamantylcarboxamidophenylalkanoicacids and lower alkyl esters can be prepared by reacting aminophenylalkanoic acids and lower alkyl esters with adamantoyl chloride orbromide in an anhydrous solvent, for instance, a mixture of benzene andan organic base, like pyridine. The preferred solvent is pyridine. Theacids or esters can be prepared from one another by subsequenthydrolysis of the esters, for instance, by means of sodium hydroxide orpotassium hydroxide or by esterification of the acids, for instance, bymeans of an esterifying agent, for example, diazomethane or an alcoholwith an acid catalyst. These re actions can be represented as follows:

| (l) R CH(CH2)Il-COOR Adamantyl-COX I l NH2 esterification =hydrogen)wherein R R R R and n have the meaning as defined in formula I and X ischlorine or bromine.

The aminophenylalkanoic acids and lower alkyl esters are prepared by thereduction of the corresponding nitro compounds, which may be preparedfrom known chemi cals by known procedures.

The compounds of the present invention demonstrate the properties ofinhibiting and reducing inflammation, and of suppressing immuneresponses in warm-blooded animals when administered orally orparenterally, and are thus useful as anti-inflammatory agents. Althoughthe mechanism of action of these anti-inflammatory agents is notcompletely understood it may at least in part be traceable to thecompounds ability to suppress antibody formation. Thus while thecompounds can be shown to demonstrate activity in classical laboratorymodels for testing anti-inflammatory properties such as theanticarrageenin test, serum turbidity test, adjuvant arthritis test, andantipyretic test, they also demonstrate immunosuppressive acivity in theJerne Hemolytic Plaque Technique.

In addition to the above properties, the compounds of the presentinvention advantageously exhibit anti-allergic effects. These can bedemonstrated in animal tests, using advantageously mammals, such asrats, guinea pigs, dogs or monkeys. Compounds of the invention can beadministered to the animals either enterally, preferably orally, orparenterally, e.g. subcutaneously, intravenously, for example, in theform of aqueous solutions, suspensions or by means of an aerosol. Theapplied dosage ranges between about 1 and 300 mg./kg./day, preferablybetween about 20 and 200/ mg./ kg./day, or more preferably between 40and mg./kg./day. The tests chosen are the guinea pig anaphylaxis, canineasthma and primate skin allergy. In each system, various standards aretested for reference purposes.

Thus, for example, the Z-(I-adamantylcarboxamido) phenyl-acetic acid, arepresentative member of the compounds of formula I, in the canineasthma model after Ia(R =lower alkyl) the induction of an asthmaticattack (therapeutic) showed 70% inhibition at 100 mg./kg./po. Whenadministered i.v. at 40 mg./kg., said compound gave 40% inhibition. Theformer effect is equivalent to that observed by theophylline. Finally,when mixed with the inducing antigen (inhalant) at 3 mg./kg., thecompound inhibited the reaction 66%. In the monkey skin allergy model,the above compound gives a dose-related inhibition of the reaction,whereas antihistamines are inactive. In the guinea pig anaphylaxismodel, pretreatment with the above compound inhibits the reactions 69%at 100 mg./kg./po. It is also noted that said compound, given afteranaphylaxis has occurred, inhibits, 1 hour later (at the time of peakblood levels), the residual bronchoconstriction which clinically resultsin delayed deaths [Collier, H.O.J. et al., Brit. J. Pharmacol.Chemotherap. 30, 283 (1967)]. Anti-histamines do not inhibit thisresidual broncho-constriction indicating that the above compound iscapable of inhibiting mediators of this reaction which are insensitiveto antihistamines. Accordingly, compounds of the invention areanti-allergic agents and are useful, for example, in the treatment ormanagement of asthma.

The preferred compounds are those defined in formula I wherein R R and Rare hydrogen, R is hydrogen, fiuoro, chloro, bromo, lower alkyl, loweralkoxy, or trifluoromethyl, n is 0, and the alkanoic acid is in theortho-position of the phenyl ring relative to the adamantylcarboxamidogroup. The following compounds are illustrative:

2- l-adamantylcarbox amido) -4-methylphenylacetic acid,

2-( l-adamantylcarboxamido) -4-trifluoromethylphenylacetic acid,

2-( l-ad amantylcarboxamido) -5-fiuorophenylacetic acid,

2- l-adamantylcarboxarnido -5-methoxyphenylacetic acid,

and, above all, the 2-( l-adarnantylcarboxamido) phenylacetic acid.

In actual use, the compounds of formula I are administered to mammalsfor the purpose of treating various inflammatory conditions which arecommonly treated with known anti-inflammatory agents, particularly thosein which an immunological mechanism is believed to be present, such asvarious forms of rheumatoid arthritis. The compounds are alsoadministered to mammals for the purpose of treating various allergicconditions, particularly of the asthmatic type. The new compounds areincorporated in compositions suitable for oral administration to mammalsin solid and liquid unit dosage forms, such as tablets, capsules,powders, granules, syrups, elixirs, and the like. The term unit dosageform as used in this specification and claims refers to physicallydiscrete units suitable as unitary dosages for mammals, each unitcontaining a predetermined quantity of active material calculated toproduce the desired therapeutic effect in association with the requiredpharmaceutical diluent carrier or vehicle. The compositions thus containabout 0.1- 75%, preferably about 1-50%, of the active ingredient.

Powders are prepared by comminuting a compound of this invention to asuitably fine size and mixing a similarly comminuted diluent. Thediluent can be an edible carbohydrate material such as starch. Asweetening agent or sugar may also be present as well as flavoring oil.

Granules for reconstitution into a liquid oral preparation are preparedutilizing water-soluble diluents. A powder mixture of the finely dividedcompound and watersolube diluent such as sucrose, glucose, and the likeis wetted with a binder such as acacia mucilage, gelatin solution,methylcellulose solution and forced through a screen to form granuleswhich are allowed to dry. A suspending agent such as tragacanth may beincluded in the composition.

Capsules are made by preparing a powder mixture as described above andfilling formed gelatin sheaths. As an adjuvant to the filling operation,a lubricant such as talc, magnesium stearate and calcium stearate may beadded to the powder mixture before the filling operation.

Tablets are made by preparing a powder mixture, granulating or slugging,adding a lubricant and pressing into tablets. The powder mixture isprepared by mixing the compound, suitable comminuted, with a diluent orbase such as starch, sucrose, kaolin, dicalcium phosphate and the like.The powder mixture can be granulated by wetting with a binder such asyrup, starch paste or acacia mucilage and forcing through a screen. Asan alternative to granulating, the powder mixture can be slugged, i.e.run through the tablet machine and the resulting imperfectly formedtablets broken into slugs. The slugs can be lubricated to preventsticking to the tablet forming dies by means of the addition of stearicacid, a stearate salt, talc or mineral oil. The lubricating mixture isthen compressed into tablets. A protective coating consisting of asealing coat of shellac, a coating of sugar and methylcellulose, and apolish coating of carnauba wax may be provided.

Oral fluids are prepared in unit dosage forms such as syrups and elixirswherein each teaspoonful of composition contains a predetermined amountof the compound for administration.

A syrup is prepared by suspending the compound in a suitably flavoredaqueous sucrose solution. Similarly, an elixir is prepared utilizing anon-toxic alcohol vehicle.

For parenteral administration, aqueous and oleaginous fluid unit dosageforms can be prepared. In preparing the parenteral form, a measuredamount of the compound is placed in a vial, the vial and its contentssterilized and sealed. An accompanying vial of sterile water may beprovided as a vehicle to form a suspension prior to administration.Particularly suitable for parenteral administration are the additionsalts of the compounds of formula I.

The amount of these compounds which is administered must in all cases beadjusted to the mammal being treated, its age, weight and condition, aswell as the degree of response required. The actual dose should becarefully titrated to the particular subject in accordance withwellrecognized principles of pharmacology.

The following examples are given by way of illustrating the process forthe preparation of the compounds and the compositions without limitingthe scope thereof in any way. The temperatures are given in degreesCentigrade.

EXAMPLE 1 Methyl 2-( l-adamantylcarboxamido) phenylacetate Twenty gramsof methyl 2-aminophenylacetate are dissolved in 150 ml. of dry pyridineand cooled to 0. 28 g. of l-adamantanecarbonyl chloride is added slowlywith vigorous stirring. On completion of the addition, the reaction isstirred at room temperature for three hours, the pyridine hydrochlorideformed during the reaction is then separated by filtration. After theaddition of water to the filtrate the desired product precipitates. Theprecipitate is separated by filtration and is recrystallized fromaqueous ethanol as colorless prisms melting at l3013l C.

EXAMPLE 2 2-( l-Adamantylcarboxamido) phenylacetic acid A mixture of23.3 g. of methyl Z-(I-adamantylcarboxamido)-phenylacetate and ml. of Nsodium hydroxide is heated under reflux until a homogeneous solution isobtained. The solution is filtered, cooled to room temperature and thepH adjusted to 3 with 6N hydrochloric acid.

A sticky white solid precipitates which is dissolved in hot ethanol.Sulficient water is then added to induce crystallization. The desiredneedles melting at 230-231 C.

EXAMPLE 3 2-( l-Adamantylcarboxamido)-4-methylphenylacetic acid (a)Twenty-three grams of sodium metal spheres are added with stirring at amoderate rate to 1 liter of absolute ethanol contained in a 5 literthree-necked flask equipped with stirrer, condenser and dropping funnel.Diethyl malonate (160.2 g.) is then added dropwise by means of thedropping funnel, followed by the addition of 171.6 g. of3-nitro-4-chlorotoluene. The mixture is heated at reflux for 2.5 hoursafter which the ethanol is distilled olf at atmospheric pressure. To thereaction flask is then added 1 liter of absolute ethanol and 1 liter ofpotassium hydroxide and the mixture is then heated at reflux for 1.5hours, followed by distillation of the ethanol at atmospheric pressure.The solution is cooled to room temperature and extacted twice with 500ml. of ether. The basic aqueous layer is adjusted to a pH of 1 by meansof 6N hydrochloric acid to yield a brown solid. The product is collectedby filtration and dried for 18 hours at 70 C./ 10 mm. The4-methyl-2-nitrophenylacetic acid melts at 1678 C.

(b) A mixture of 17.5 g. of 4-methyl-2-nitrophenylacetic acid, 250 ml.of absolute methanol and 5 ml. of concentrated sulfuric acid is heatedat reflux for 2 hours, then excess solvent is removed by distillation.The reaction is cooled to room temperature, rendered basic with a 10%ammonium hydroxide solution, diluted with 500 ml. of water and twiceextracted with 300 ml. of ether. The ether extracts are dried overmagnesium sulfate, clarified, filtered, and evaporated to dryness underreduced pressure to yield methyl 4-methyl-Z-nitrophenylacetate as anamber-colored oil.

(c) The oil obtained according to part (b) of this Example is dissolvedin 1.50 ml. of ethyl acetate and 1 g. of 5% palladium on carbon as addedas catalyst. The reaction mixture is hydrogenated at atmosphericpressure until three molar equivalents of hydrogen are consumed. Thecatalyst is removed by filtration and the filtrate is evaporated todryness under reduced pressure at 30-35 C., yielding methyl2-amino-4-methylphenylacetate as an oil.

(d) To a stirred solution of 7.5 g. of methyl 2-amino-4-methylphenylacetate in 150 ml. of dry pyridine is added 8.4 g. ofl-adamantanecarbonyl chloride in one portion, maintaining a reactiontemperature of from 25 to 30 C. The mixture is stirred for minutesduring which time pyridinium chloride separates out. The mixture isdiluted with 200 ml. of water and the precipitate is collected byfiltration to yield methyl 2-(l-adamantylcarboxamido)-4-methylphenylacetate, m.p. 144-5 C.

(e) A mixture of 12.1 g. of a compound according to part (d) of thisExample and 150 ml. of 0.5N sodium hydroxide solution is heated underreflux until a homogeneous solution is obtained. The solution is cooledto C., filtered and adjusted to a pH of 4 with 3N hydrochloric acid. Thesolid is collected by filtration and is recrystallized from aqueousethanol as colorless plates, m.p. 214-215 C.

EXAMPLE 4 2-( l-Adamantylcarboxamido)-4-trifiuoromethylphenylacetic acid(a) To a mixture of 17.7 g. of methyl2-amino-4-trifluoromethylphenylacetate in 200 ml. of dry pyridine areadded 15.1 g. of l-adamtanecarbonyl chloride in one portion. The mixtureis kept at 20 C. and is agitated for five minutes at which timepyridinium chloride separates. The reaction mixture is diluted with 400ml. of water. With further agitation, the product precipitates. Thesolid is collected by filtration, washed twice with 50 ml. of water anddried in vacuo. The obtained methyl Z-(I-adamantylmelts at EXAMPLE 5 2-(1-Adamantylcarboxamido)-5-fluorophenylacetic acid (a) A mixture of 10 g.of S-fluoro-2-nitrophenylacetonitrile and 75 ml. of concentratedhydrochloric acid is heated at reflux for minutes. The reaction mixtureis poured into 300 ml. of cold water with stirring whereupon the5-fluoro-Z-nitrophenylacetic acid precipitates. The solid is collectedby filtration and is dried in vacuo, m.p. 1515 C.

(b) A mixture of 8.1 g. of 5-fluoro-2-nitrophenylacetic acid, 150 ml. ofabsolute methanol and 5 ml. of concentrated sulfuric acid is heated atreflux for two hours. Excess methanol is evaporated, the residue isdiluted with 200 ml. of water, and the solution is rendered basic with a10% ammonium hydroxide solution. The basic aqueous layer is extractedtwice with 200 ml. of ether. The ethereal extracts are clarified, driedover magnesium sulfate, and the solvent evaporated under reducedpressure to yield methyl 5-fluoro-2-nitrophenylacetate as an oil.

(c) To 7.7 g. of methyl S-fluoro-Z-nitrophenylacetate, dissolved in 200ml. of absolute ethanol, are added 1 g. of 5% palladium on bariumsulfate. The mixture is bydrogenated at atmospheric pressure and at 20C. until three molar equivalents of hydrogen are consumed. The catalystis removed by filtration and the filtrate is evaporated to dryness underreduced pressure to yield methyl 5- fluoro-Z-aminophenylacetate as anoil.

(d) A mixture is prepared by dissolving 6.4 g. of methyl5-fluoro-2-aminophenylacetate in 150 ml. of dry pyridine. 7.2 g. ofl-adamantanecarbonyl chloride are added to the stirring pyridinesolution in one portion. The mixture is stirred vigorously for 3 to 5minutes and is then diluted with 400 ml. of Water precipitating a solidwhich is methyl 2-(l-adamantylcarboxamido)-5-fluorophenylacetate. Theproduct is collect-ed by filtration, washed with water and dried, m.p.-142 C.

(e) A mixture of 11.1 g. of methyl2-(l-adamantylcarboxamido)-5-fluorophenylacetate and 200 ml. of 0.5Nsodium hydroxide is heated at refluxing temperature until a homogeneoussolution is obtained. The solution is clarified, filtered, diluted with250 ml. of water, cooled to room temperature and rendered acid to a pHof 4 with 6N hydrochloric acid. The product is collected by filtrationand is recrystallized from aqueous ethanol as colorless needles, m.p.247248 C.

EXAMPLE 6 2-( l-Adamantylcarb oxamido -5-methoxyphenylacetic acid (a)5-Methoxy-2-nitrophenylacetic acid is prepared according to theprocedure described by C. F. Koelsch,

J. Am. Chem. Soc. 66, 2019-20 (1944).

(b) After dissolving 33 g. of 5-meth0xy-2-nitrophenylacetic acid in 200ml. of absolute methanol, 5 ml. of concentrated sulfuric acid are added.The mixture is heated at reflux for two hours. Excess solvent is removedby distillation, the residue is diluted with 550 ml. of water, and thesolution is rendered basic with 10% ammonium hydroxide. The aqueoussolution is extracted with ether (3x 300 ml.). The ethereal extracts areclarified, dried over magnesium sulfate, and the solvent evaporatedunder reduced pressure to yield a solid 'which is methyl 5-methoxy-Z-nitrophenyl-acetate, m.p. 162l64 C.

(c) 34.1 g. of Methyl S-methoxy-2-nitrophenylacetate is dissolved in 200ml. of ethyl acetate and 3 g. of 5% palladium on barium sulfate is addedas catalyst. The mixture is hydrogenated at atmospheric pressure at 20C., until three molar equivalents of hydrogen have been consumed. Thecatalyst is separated by filtration and the filtrate is evaporated todryness under reduced pressure to yieldmethyl-S-methoxy-2-aminophenylacetate as an oil.

(d) To a mixture of 9.7 g. of methyl 5-methoxy-2- aminophenylacetate in80 ml. of dry pyridine are added 9.9 g. of l-adamantanecarbonyl chloridewhile stirring. After a new minutes, pyridinium chloride precipitates.The mixture is allowed to stir at room temperature for ten minutes; thenthe mixture is diluted with 300 ml. of water whereupon methyl2-(l-adamantylcarboxamido)-5- methoxy-phenylacetate precipitates. Thesolid is collected by filtration and is washed twice with 100 ml. ofwater. The crude product melts at 163165 C.

(e) A mixture of 22 g. of methyl2-(1-adamantylcarboxamido)-5-methoxyphenylacetate and 150 ml. of 0.5Nsodium hydroxide is heated at reflux until a homogeneous solution isobtained. The solution is clarified, filtered, diluted With 200 ml. ofwater, cooled to room temperature and rendered acid with 3N hydrochloricacid to a pH of 4. The solid is collected by filtration, washed withwater and recrystallized from aqueous ethanol, m.p. 188-189 C.

EXAMPLE 7 2-( l-Adamantylcarboxamido)-4,5- dimethoxyphenylacetic acid(a) The starting material methyl 2 amino 4,5 dimethoxyphenylacetate isprepared according to the procedure described by G. N. Walker, I. Am.Chem. Soc. 77, 3844-50 (1955).

(b) To a stirring mixture of 21.8 g. of methyl 2-amino-4,S-dimethoxyphenylacetate in 150 ml. of dry pyridine are added19.2 g. of l-adamantanecarbonyl chloride while maintaining the reactiontemperature at 30 C. by means of an ice-water bath. The reaction mixtureis agitated for 10 minutes at room temperature at which time it isdiluted with 400 ml. of water upon which a viscous oil separates. Theaqueous layer is decanted and the residual oil is solidified upontrituration with 150 ml. of ether and scratching. The product iscollected by filtration and is recrystallized from aqueous ethanol toyield methyl 2-( l-adamantylcarboxamido) -4,5-dimethoxyphenylacetatemelting at 149-150 C.

(c) A mixture of 16.5 g. of methylZ-(I-adamantylcarboxamido)-4,S-dimethoxyphenylacetate and 200 ml. of0.5N sodium hydroxide solution is heated at reflux until a homogeneoussolution is obtained. The hot solution is clarified, filtered and cooledto room temperature. The solution is then adjusted to pH 4 with 3Nhydrochloric acid whereupon a solid precipitates. The solid is collectedby filtration and is recrystallized from aqueous ethanol, m.p. 230232 C.

EXAMPLE 8 2- 2- l-Adamantylcarboxamido phenyl] propionic acid (a) To asolution of 10.2 g. of methyl a-methyl-o-nitrophenylacetate in 150 ml.of ethyl acetate, there is added 1.5 g. of 5% palladium on bariumsulfate as catalyst. The mixture is hydrogenated at atmospheric pressureand room temperature until three molar equivalents of hydrogen areconsumed. The catalyst is removed by filtration and the solvent isevaporated to dryness under reduced pressure at 30 C. Methylot-methyl-o-aminophenylacetate in form of an amber oil is obtained.

(b) A solution of 8.3 g. of methyl a-methyl-o-aminophenylacetate in 150ml. of pyridine is cooled and stirred while 9.14 g. ofl-adamantanecarbonyl chloride are added. After 5 hours a small quantityof water is added, the mixture is left to stir at room temperature for18 hours, is diluted with 200 ml. of water and is rendered basic with a5% sodium bicarbonate solution. The reaction product is extracted withether. The ethereal extracts are dried and the solvent evaporated todryness to yield methyl 2 [2 (l-adamantylcarboxamido)phenyl] propionate,m.p. 97-99 C.

(c) The methyl 2 [2 (1 adamantylcarboxamido) phenyl]propionate obtainedaccording to part (b) of this Example is mixed with 0.1 N sodiumhydroxide and the mixture heated at reflux until a homogeneous solutionis obtained. The solution is clarified, filtered, cooled, and the pHadjusted to 1. The desired product precipitates. The solid is collectedby filtration and is recrystallized from aqueous ethanol, m.p. 190-192C.

EXAMPLE 9 Methyl 2-[2- l-adamantylcarboxamido)-4-trifluoromethylphenyl]propionate (a) To an ice-bath cooled solution of 40.0 g. of methyl2-nitro-4-trifluoromethylphenylacetate in 250 ml. of dimethylformamide,there is added 6.4 g. of 57% oil dispersion of sodium hydride followedby the addition of 107.9 g. of methyl iodide. The mixture is heated at40 C. until the color of the solution changed to a deep yellow. Thesolution is poured into ice-water, extracted into ether and the etherealsolution is washed with water, dried, clarified and filtered. Thesolvent is evaporated to dryness under reduced pressure. Methyl2-(2-nitro-4-trifluoromethylphenyl)propionate in form of a yellow oil isobtained.

(b) To a solution of 42.5 g. of methyl 2-(2-nitro-4-trifluoromethylphenyl)propionate in 300 ml. of ethyl acetate, there isadded 5.2 g. of 5% palladium on barium sulfate as catalyst. The mixtureis hydrogenated at atmospheric pressure and room temperature until threemolar equivalents of hydrogen are consumed. The catalyst is removed byfiltration and the solvent is evaporated to dryness under reducedpressure at 30 C. Methyl 2-(2-amino-4-trifluoromethylphenyl)propionatein form of a pale yellow oil is obtained.

(c) To a stirred solution of 16.6 g. of methyl 2-(2-amino-4-trifluoromethylphenyl)propionate in 100 ml. of dry pyridine isadded 13.9 g. of l-adamantanecarbonyl chloride in one portion,maintaining a reaction temperature of 30-40 C. The mixture is stirredfor one hour during which time pyridinium chlorine separates out. Themixture is diluted with 400 ml. of water and the precipitate iscollected by filtration. The solid is recrystallized from aqueousethanol to yield methyl 2-[2-(1-adamantylcarboxamido) 4trifluoromethylphenyl]propionate as colorless plates, m.p. 121-122 C.

EXAMPLE 10 2- [2- l-Adamantylcarboxamido -4-trifluoromethylphenyl]propionic A mixture of 19.2 g. of methyl 2-[2-(l-adamantylcarboxamido) 4trifluoromethylphenyl]propionate and 400 ml. of 0.45N sodium hydroxidesolution is heated under reflux until a homogeneous solution isobtained. The solution is cooled and extracted twice with 250 ml. ofether. The aqueous layer is then rendered acid to pH 1 with 6Nhydrochloric acid and the precipitate collected by filtration. The solidis recrystallized from aqueous ethanol to yield2-[2-(l-adamantylcarboxamido)-4-trifluoromethylphenyl]propionic acidmelting at 2l52l6 C.

EXAMPLE 1 1 Methyl 2-[2-l-Adamantylcarboxamido)-4-trifluoromethylphenyl] hexanoate (a) To anice-bath cooled solution of 27.5 g. methyl 2 nitro 4trifluoromethylphenylacetate in 200 ml. of dimethylformamide, there isadded 4.4 g. of 57% oil dispersion of sodium hydride followed by theaddition of 28.5 g. of n-bromobutane. The mixture is heated at C. untilthe color of the solution changed to a deep yellow. The solution ispoured into ice-water, extracted into ether and the ethereal solution iswashed with water, clarified, dried and filtered. The solvent isevaporated to dryness under reduced pressure at 30 C. Methyl 2-(2-nitro-4-trifluoromethylphenyl)hexanoate in form of an amber oil isobtained. The amber oil is distilled under reduced pressure (0.005 mm.)and at 100-103 C. to yield 19.5 g. of a yellow oil.

(b) To a solution of 19.5 g. of methyl 2-(2-nitro-4-trifluoromethylphenyl)hexanoate in 250 ml. of ethylacetate, there isadded 3.5 g. of 5% palladium on barium sulfate as catalyst. The mixtureis hydrogenated at atmospheric pressure and room temperature until threemolar equivalents of hydrogen are consumed. The catalyst is removed byfiltration and the solvent is evaporated to dryness under reducedpressure at 30 C. Methyl 2-(2-amino-4-trifiuoromethylphenyl)hexanoate inform of a pale yellow oil is obtained.

(c) To a stirred solution of 17.6 g. of methyl 2-(2-amino-4-trifluoromethylphenyl)hexanoate in 50 ml. of dry pyridine isadded 12.3 g. of l-adamantanecarbonyl chloride in one portion,maintaining a reaction temperature of from 30-45 C. The mixture isstirred for one hour during which time pyridium chloride separates out.The mixture is diluted with 400 ml. of water and the precipitate iscollected by filtration. The solid is recrystallized from aqueousethanol to yield methyl 2-[2-(1-adamantylcarboxamido) 4trifluoromethylphenyl]hexanoate as colorless crystals, m.p. 127-128 C.

EXAMPLE 12 2- [2-( l-Ad amantylcarboxamido -4-trifiuoromethy1-phenyl]hexanoic acid A mixture of 18.7 g. of methyl2-[2-(1-adamantylcarboxamido)-4-trifluoromethylphenyl]hexanoate, 32.8 g.of sodium bicarbonate, 300 ml. of methanol and 20 ml. of water is heatedat 80 C. for 18 hours. The solution is evaporated to dryness underreduced pressure and is diluted with 400 ml. of water. The solution isextracted twice with 250 ml. of ether and the aqueous layer is renderedacid to pH 1 with 6N hydrochloric acid. The aqueous layer is extractedwith ether and the ethereal solution is washed with water, charcoaled,dried and filtered. The solvent is evaporated to dryness and the solidobtained recrystallized from ether-petroleum ether (b.p. 3040 C.) toyield 2-[2-(l-adamantylcarboxamido)- 4- trifluoromethylphenyllhexanoicacid melting at 170- 171.5 C.

EXAMPLE 13 Sodium 2-( l-adam antylc arb oxamido phenylactate 7.8 g. ofthe compound of Example 2 was dissolved in ca. 200 m1. of methanol and1.34 g. of sodium methoxide was added to the solution. The solvent wasthen removed by evaporation under reduced pressure to yield a whitefoam. The product was crystallized twice by suspending the solid in hotacetone (100 ml.) and adding methanol (ca. 20 ml.) to effect solution.The product crystallized overnight at room temperature, m.p. 237-240 C.

EXAMPLE 14 2-( l-Adamantylcarboxamido)phenylacetic acid A2-aminophenylacetic acid (3.02 g.) is dissolved in dry pyridine (50 ml.and cooled to 0", and l-adamantane carbonyl chloride (3.97 g.) is addedslowly with vigorous stirring. On completion of the addition, thereaction is stirred at room temperature for 1 hour, the pyridinehydrochloride formed during the reaction is then separated byfiltration. After the addition of Water (250 ml.) to the filtate thedesired product is extracted into chloroform (250 ml.). The chloroformextract is washed with water (750 ml.; 3 X 250 ml.) and dried overmagnesium sulfate and the solvent is evaporated under reduced pressure.The product is purified by partitioning the crude material betweensodium bicarbonate solution and ether. The aqueous solution is separatedand acidified with 6N hydrochloric acid, whereby the productprecipitates as a sticky white solid, which is collected by filtration.The desired product is recrystallized from aqueous ethanol as colorlessneedles melting at 230-231 C.

EXAMPLE l5 3- l-Adamantylcarboxamido)phenylacetic acid (a) A mixture isprepared from 10 g. of methyl 3- aminophenylacetate and ml. of drypyridine, and 10.2 g. of l-adamantanecarbonyl chloride are added in oneportion to the stirring solution. The reaction is stirred for 10 minutesat which time it is diluted with 300 m1. of water precipitating methyl3-(l-adamantylcarboxamido)phenylacetate as a white solid. The product iscollected by filtration, washed with water (3X 100 ml.) and dried invacuo, m.p. 132-133 C.

(b) A mixture of 16.4 g. of methyl3-(l-adamantylcarboxamido)phenylacetate and 200 ml. of 0.5N sodiumhydroxide solution is heated at reflux until a homogeneous solution isobtained. The solution is filtered, the filtrate diluted with 400 ml. ofwater and the pH adjusted to 4 with 6N hydrochloric acid whereupon thedesired product precipitates. The product is collected by filtration,washed with water (3x 100 ml.) and recrystallized from aqueous ethanol,m.p. 203-204 C.

EXAMPLE 16 4- l-Adamantylcarboxamido) phenylacetic acid (a) To a mixtureof 16.5 g. of methyl 4-aminophenylacetate in 100 ml. of dry pyridine areadded 19.5 g. of l-adamantanecarbonyl chloride while maintaining thereaction temperature between 25-30 C. On completion of addition,pyridinium chloride separates out and the reaction mixture is stirredfor further 15 minutes at room temperature after which time it isdiluted with 200 ml. of water yielding methyl4-(l-adamantylcar-boxamido) phenylacetate as a copious preciptate. Thesolid is collected by filtration and dried, m.p. l55l56 C.

(b) A mixture of 18 g. of methyl 4-(1-adamantylcarboxamido)phenylacetateand 200 ml. of 0.5N sodium hydroxide is heated at reflux until ahomogeneous solution is obtained. The solution is cooled to 35 C. andthe sodium salt separates out. The solid is collected by filtration andis dried in vacuo. The sodium salt is recrystallized from water, m.p.294-295 C. The salt is then dissolved in 250 ml. of water and thesolution is adjusted to pH 4 by means of 3N hydrochloric acid. Theformed acid is collected by filtration and recrystallized from aqueousethanol to yield the desired product in form of colorless plates, m.p.193-194 C.

EXAMPLE 17 3-[2-( l-Adamantylcarboxamido) phenylJpropionic acid (a) Asolution of 23.4 g. of methyl-o-aminocinnamate in 200 ml. of pyridine isstirred while 26.2 g. of 1- adamantanecarbonyl chloride are added. Thereaction mixture is stirred at room temperature for 15-20 minutes and isthen diluted with 500 ml. of water yielding a precipitate. Thesuspension is left stirring overnight at room temperature. The solid iscollected by filtration and is recrystallized from aqueous ethanol. Therecrystallized material is collected by filtration and is washed withcold ether to yield methyl 2-(l-adamantylcarboxamido)cinnamate as anoff-white colored solid, m.p. -172 C.

(b) To a solution of 8.5 g. of methylZ-(I-adamantylcarboxarnido)cinnamate in 200 ml. of absolute ethanol and5 ml. of glacial acetic acid, there is added 1.5 g. of 5% palladium onbarium as catalyst. The mixture is hydrogenated at atmospheric pressureand room temperature until one molar equivalent of hydrogen is consumed.The catalyst is removed by filtration and the filtrate is evaporated todryness to yield methyl 3-[2-(l-adamantylcarboxamido)phenyl]propionate,m.p. 106108 C.

(c) A mixture of 7.8 g. of methyl3-[2-(1-adamantylcarboxamido)phenyl]propionate and 300 ml. of 0.1Nsodium hydroxide is heated at reflux until a homogeneous solution isobtained. The solution is clarified, filtered, cooled, and rendered acidwith 6N hydrochloric acid to pH 1 yield the desired product in form of awhite precipitate. The solid is collected by filtration and isrecrystallized from aqueous ethanol as colorless plates, mp. 192- 193 C.

EXAMPLE 18 Ingredient: Quantity/capsule (mg.)

2- 1-Adamanty1carboxamido)- phenylacetic acid 100 Corn starch, U.S.P.200

The foregoing ingredients are mixed and introduced into a two-piece No.1 hard gelatin capsule.

EXAMPLE 19' Ingredient: Quantity/tablet (mg.)

Methyl 2- l-adamantylcarboxamido)phenylacetate 50 Corn starch, U.S.P.130 Lactose 160 Cab-O-Sil M- 4 Gelatin U.S.P. 5 Magnesium stearateU.S.P. 1

The foregoing ingredients are thoroughly mixed and pressed into tabletssuitable for oral administration of 50 g. of active ingredient. Thetablets may be scored to permit administration of fractional doses.

EXAMPLE 20 Ingredient: Quantity/tablet (mg.)

2-( l-Adamantylcarboxamido phenylacetic acid 100 Lactose 80 Corn starchSoluble starch 15 Magnesium stearate 5 The first three ingredients arethoroughly mixed and granulated with a solution of the soluble starch.This granulate is dried, mixed with the magnesium stearate and pressedinto tablet cores which are coated as with sugar.

I claim:

1. A compound of the formula Jill-(CH -coon wherein R is hydrogen orlower alkyl;

R is hydrogen or lower alkyl;

R and R are hydrogen, fluorine, chlorine, bromine lower alkyl, loweralkoxy, or tribuoromethyl; and

n is 0 or 1.

2. A compound as defined in claim 1 wherein R R and R are hydrogen, R ishydrogen, fluorine, chlorine, bromine, lower alkyl, lower alkoxy, ortrifiuoromethyl, n is zero and the alkanoic acid group is in 2-positionof the phenyl ring.

3. A compound as defined in claim 1 wherein said compound is2-(1-adamantylcarboxamido)phenylacetic acid.

4. A compound as defined in claim 1 wherein said compound is2-(l-adamantylcarboxamido) 4 methylphenylacetic acid.

5. A compound as defined in claim 1 wherein said compound is 2-(l-adamantylcarboxamido) 4 trifiuoromethylphenylacetic acid.

6. A compound as defined in claim 1 wherein said compound is 2 (1adamantylcarboxamido) 5 fluorophenylacetic acid.

7. A compound as defined in claim 1 wherein said compound is2(l-adamantylcarboxamido) 5 methoxyphenylacetic acid.

References Cited UNITED STATES PATENTS 3,766,262 10/1973 Szinaiet a1260-518 R LORRAINE A. WEINBERGER, Primary Examiner L. A. THAXTON,Assistant Examiner US. Cl. X.R.

1. A COMPOUND OF THE FORMULA